Androstane-17beta-carboxylic acids and processes for the preparation thereof

ABSTRACT

THE SPECIFICATION DESCRIBES NEW ANDROSTANE COMPOUNDS HAVING ANTI-INFLAMMATORY ACTIVITY. THE NEW ANDROSTANCES DESCRIBED IN THE SPECIFICATION HAVE AN ESTERFIELD 17B-CARBOXYLICC ACID GROUPING WHEREIN THE ALCOHOL RESIDUE COMPRISES EITHER AT LEAST ONE HALOGEN ATOM OR A LOWER ALKOXYBY EITHER AT LEAST ONE HALOGEN ATOM OR A LOWER ALKOXYCARBONYL GROUP OR A (C2-4) LOWER ALKYL GROUP SUBSTITUTED BY A LOWER ACYLOXY GROUP. THE 17A-GROUPING OF THESE ANDROSTANCES IS AN ESTERIFIED HYDROXY GROUP COMPRISING A FORMLY, C2-4 ALKANOYL OR BENZOYL GROUP.

United States PatentOfice 3,828,080 Patented Aug. 6, 1974 US. Cl.260--397.1

ABSTRACT OF THE DISCLOSURE The specification describes new androstanecompounds having anti-inflammatory activity. The new androstanesdescribed in the specification have an esterified l7,8-carboxylic acidgrouping wherein the alcohol residue comprises a lower alkyl group; alower alkyl group substituted by either at least one halogen atom or alower alkoxycarbonyl group; or a (C lower alkyl group substituted by alower acyloxy group. The 17a-grouping of these androstanes is anesterified hydroxy group comprising a formyl, C alkanoyl or benzoylgroup.

This invention is concerned with steroid compounds havinganti-inflammatory properties.

Since the discovery of cortisone, a wide variety of compounds ofanalogous structure have been prepared having anti-inflammatoryproperties, such compounds being generally members of the pregnaneseries.

Anti-inflammatory steroids have found wide use in medicine and in latteryears considerable attention has been directed to compounds having highanti-inflammatory action on topical administration.

Auto-inflammatory steroids of the pregnane series so far described,being generally analogous to cortisone, tend to a greater or lesserextent to exert the physiological action of the natural hormone and thuspossess, in addition to anti-inflammatory action other actions similarto cortisone-like compounds. The physiological effects of thepregnane-type anti-inflammatory steroids may be broadly classified asglucocorticoid and mineralocorticoid effects, anti-inflammatory actionat least until recently having been regarded as a glucocorticoid action.Glucocorticoid efi'ects also include general disturbance of the bodymetabolism and may be very undesirable. Mineralocorticoid effectsinvolve disturbance of the salt and water balance within the body andcompounds having marked mineralocorticoid action are thus likely toproduce undesirable effects on administration.

Even in the topical application of anti-inflammatory steroids, there isa risk that the steroid may be absorbed into the system through theskin, with subsequent development of undesired side effects.

There is thus a general desire to have available an antiinflammatorysteroid with high anti-inflammatory action but with which the undesiredeffects, either mineralocorticoid or glucocorticoid in nature, arereduced.

We have now found that certain new steroids of the androstane series,possess marked anti-inflammatory action. Moreover our researchesindicate that generally the ratio of anti-inflammatory action toundesired cortisonelike action in our new compounds is generally good.

The steroid compounds with which the invention is concerned arecompounds of the general formula wherein (a) X represents a hydrogen,chlorine or fluorine atom; R represents a hydroxy group in thefi-configuration or (when X represents a chlorine atom) R may alsorepresent a chlorine atom in the lit-configuration; R represents ahydrogen atom, a methylene group or a methyl group (in either the aorIii-configuration); R represents a hydrogen atom, an alkyl groupcontaining 1 to 3 carbon atoms or a phenyl group; R represents a loweralkyl group; a lower alkyl group substituted by either at least onehalogen atom or a lower alkoxy carbonyl group; or a (C lower alkyl groupsubstituted by a lower acyloxy group; and represents a single or doublebond; or

(b) X represents a chlorine or fluorine atom; R represents an oxo group;R represents a hydrogen atom, a methylene group or a methyl group (ineither the aor fl-configuration); R represents a methyl or ethyl group;R represents a lower alkyl group; a lower alkyl group substituted byeither at least one halogen atom or a lower alkoxycarbonyl group; or a(C lower alkyl group substituted by a lower acyloxy group; andrepresents a single or double bond.

The new androstane compounds have anti-inflammatory action on topicaland internal administration, the anti inflammatory activity of thecompounds on topical administration being generally high.

In general, the group R in formula I is preferably an alkyl groupcontaining up to 3 carbon atoms, i.e. a methyl, ethyl, n-propyl oriso-propyl group. In compounds wherein R represents a hydrogen atom Rpreferably represents a methyl group.

The group R in formula I is preferably an alkyl group containing 1 to 4carbon atoms, advantageously a methyl, ethyl or propyl group.

In regard to the possible substituents of the lower alkyl group, thehalogen atom is preferably a fluorine, chlorine or bromine atom, thelower (e.g. C acyloxy group is preferably an acetoxy group and thealkoxycarbonyl group (wherein the alkoxy group advantageously contains 1to 4 carbon atoms) is advantageously, a methoxycarbonyl group.

Generally compounds of formula I in which R represents a B-hydroxy groupare preferred. Also in general terms, compounds of formula I in which Rrepresents a methyl group in .the B-configuration are preferred onaccount of their high topical anti-inflammatory activity.

A preferred class of compounds of formula I having particularly goodtopical anti-inflammatory activity with a favourable ratio of topicalanti-inflammatory activity to glucocorticoid activity are those compoundwherein X represents a chlorine or fluorine atom preferably a fluorineatom), R represents a fl-hydroxy group, R represents 1; f'giszhogo.

represents a methyl, ethyl or n-propyl group, R represents a methylgroup and represents a double bond. A further preferred class ofcompounds of formula I also having good topical anti-inflammatoryactivity with a favourable ratio of topical anti-inflammatory activityto glucocorticoid activity are those wherein X represents a fluorine orchlorine atom (preferably a fluorine atom), R represents a keto group, Rrepresents a methyl group in the fl-configuration, R represents a methylor ethyl group, R represents a methyl group and represents a doublebond.

Yet another preferred class of compounds of formula I having hightopical anti-inflammatory activity are those wherein X represents afluorine or chlorine atom (preferably a fluorine atom), R represents afi-hydroxy group, R represents a methylene group, R represents a methyl,ethyl n-propyl or iso-propyl group, R represents a methyl or ethyl group(preferably a methyl group) and preferably represents a double bond.

A preferred class of A compounds of formula I (i.c. compounds whereinrepresents a single bond) having especially good topicalanti-inflammatory activity and ratio of topical anti-inflammatoryactivity to glucocorticoid activity are those wherein X represents afluorine or chlorine atom (preferably a fluorine atom), R represents afi-hydroxy group, R represents a methyl group (preferably in thefi-configuration), R represents a methyl, ethyl or n-propyl group and Rrepresents a methyl or ethyl group (preferably a methyl group).

A still further class of compounds of formula I having good topicalanti-inflammatory activity are those wherein X represents a hydrogenatom, R represents a fi-hydroxy group and R preferably represents ahydrogen atom or a methyl group (especially in the fi-configuration) Rpreferably represents an alkyl group containing, 1,2 or 3 carbon atoms,R preferably represents a lower alkyl group (eg. a methyl group) andpreferably represents a double bond. Indeed, those compounds of thisclass wherein R represents a methyl group in the fi-configuration havebeen found to possess especially high topical anti-inflammatoryactivity.

Yet another class of compounds of formula I having good topicalanti-inflammatory activity and a good ratio of topical anti-inflammatoryactivity to glucocorticoid activity are those wherein X and R representchlorine atoms, R represents a methyl group preferably in thea-configuration, R represents a methyl or ethyl group, R represents amethyl or ethyl group and preferably represents a double bond.

Individual preferred androstanes which have been found to haveespecially good topical anti-inflammatory activity with generally lowlevels of glucocorticoid activity include:

methyl 17 a-acetoxy-9a-fluoro-l 1 B-hydroxy-l 6 B-methyl-3-oxo-androsta-1,4-diene-17,8-carboxylate methyl 9a-fluoro- 1 lfi-hydroxyl 6B-methyl-3-oxo- 17apropionyloxy-androsta-1,4-diene-l7B-carboxylate methyl 17a-butyryloxy-9afluoro-l l B-hydroxy-l 6 [3-methyl-3-oxoandrosta-1,4-diene-17B-carboxylate methyl 1741-acetoxy-9a-fluoro-1 l B-hydroxy-l 6 tat-methyl 3-oxoandrosta- 1,4-diene- 17 p-carboxylate methyl Qa-fluoro-IlB-hydroxy-16a-methyl-3-oxo- 1711- propionyloxyandrostal,4-diene l7,8-carboxylate methyl 17a-butyryloxy-9a-fluoro-1 lB-hydroxy-16amethyl-3-oxoandrosta- 1 ,4-diene- 17,6-carboxylate Ipropionyloxyandrosta-l,4-diene-17B-carboxylate methyl 9a-fll1010- l 1fi-hydroxy- 1 6 p-methyl-Ii-oxo: 17apropionyloxyandrost-4-enel 78-carboxylate ethyl 9a-fluoro-llp-hydroxy-l6fl-methyl-3-oxo-17u-propionyloxyandrosta-1,4-diene-17fl-carboxylatemethyl 17a-acetoxy-9a, 1 le-dichloro-l 6u-methyl-3oxomethyl 9a-flHOI'O-l1fi-hydroxy-l7u-isobutyryloxy-16-methylene-3-oxo-androsta-l,4-diene-l7,8-carboxylate ethyl 9a-fiuoro- 1lp-hydroxy-17a-isobutyryloxy-16-methylene-3-oxo-androsta-1,4-diene-l'lp-carboxylate and methyl1IB-hydroxy-16B-methyl-3-oxo-l7u-propionyloxyandrosta-l,4-diene-l7fl-carboxylate.

The invention further includes the compound2'-hydroxyethyl-9a-fiuoro-1lB-hydroxy 16/3 methyl-3-oxo- 17apropionyloxyandrosta-l,4-diene 17B carboxylate which is useful as anintermediate for the preparation of the corresponding halogensubstituted alkyl derivatives and moreover has topical anti-inflammatoryactivity.

There are also provided pharmaceutical compositions for use inanti-inflammatory therapy, comprising at least one androstane compoundof formula I (as defined above), together with one or morepharmaceutical carriers or excipients. Such compositions may be in formsadapted for topical or internal administration.

The active androstane compound may be formulated into a preparationsuitable for topical administration with the aid of a topical vehicletherefor. Examples of various types of preparation for topicaladministration, include ointments, lotions, creams, powders, drops (e.g.eye or ear drops), sprays (e.g. for the nose or throat), suppositories,retention enemas, chewable or suckable tablets or pellets (e.g. for thetreatment of aphthous ulcers) and aerosols. Ointments and creams may forexample, be formulated with an aqueous or oily base with the addition ofsuitable thickening and/or gelling agents, and/ or glycols. Such basemay thus, for example, include water and/or an oil such as liquidparafiin or a vegetable oil such as arachis oil or castor oil, or aglycolic solvent such as propylene glycol or 1,3-butane-diol. Thickeningagents which may be used according to the nature of the base includesoft paraffin, aluminium stearate, cetostearyl alcohol, polyethyleneglycols, woolfat, hydrogenated lanolin and beeswax and/or glycerylmonostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also include one or more of the following namely, emulsifyingagents, dispersing agents, suspending agents, thickening agents,colouring agents and perfumes.

Powders may be formed with the aid of any suitable powder base, e.g.talc, lactose or starch. Drops may be formulated with an aqueous basealso comprising one or more dispersing agents, suspending agents orsolubilising agents, etc.

Spray compositions may for example be formulated as aerosols with theuse of a suitable propellant, e.g. dichlorodifluoromethanc ortrichlorofluoromethane.

The proportion of active androstane compound in the topical compositionsaccording to the invention depends on the precise type of formulationsto be prepared but will generally be within the range of from 0.0001 to5.0% by weight. Generally however for most types of preparationsadvantageously the proportion used will be Within the range of from0.001 to 0.5% and preferably 0.01 to 0.25%.

Topical preparations may be administered by one or more applications perday to the affected area; over skin areas occlusive dressings may oftenbe used with advantage.

For internal administration the new compounds according to the inventionmay, for example, be formulated for oral parenteral or rectaladministration. For oral administration, syrups, elixirs, powders andgranules may be used which may be formulated in conventional manner.Dosage unit forms are however preferred as described below.

For parenteral administration the compounds may be presented in sterileaqueous or oily vehicles, suitable oily vehicles including arachis oil,olive oil, etc.

Preferred forms of preparation for internal administration are dosageunit forms, i.e., presentations in unitary form in which each unitcontains a desired dose of the active steroid. Such dosage unit formscontain from 0.05 to 2.0 mg, preferably from 0.25 to 1.0 mg. of theactive steroid. For oral administration suitable dosage unit formsinclude tablets, coated tablets and capsules. For parenteraladministration dosage unit forms include sealed ampoules or vials eachcontaining a desired dose of the steroid. Suppositories, which may beprepared for example with conventional commercial suppository bases,provide a dosage unit form for rectal administration. Sterile tablet orpellet implants may also be used, e.g. where slow systemic absorption isdesired.

The compounds according to the invention may in general be given byinternal administration in cases where systemic adreno-cortical therapyis indicated.

In general terms preparations for internal administration may containfrom 0.01 to 5.0% of active ingredient dependent upon the type ofpreparation involved. The daily dose may vary from 0.05 to 10.0 mg.dependent on the condition being treated and the duration of treatmentdesired.

The compositions according to the invention may also include one or morepreservatives or bacteriostatic agents, e.g., methyl hydroxy benzoate,propyl hydroxy benzoate, chlorocresol or benzalkonium chlorides. Thecompositions according to the invention may also contain other activeingredients such as antimicrobial agents, particularly antibiotics, suchas neomycin.

The compounds of formula I (as defined above) may be generally preparedby esterifying a corresponding 17amonoester 17B-carboxylic acid (orfunctional equivalent thereof) or l7a-hydroxy 17fl-carboxylate toproduce the desired compound of formula I.

As is well known to those skilled in the art it may frequently beconvenient to elaborate the desired substituents in the 17aand NB-positions at an intermediate stage of the preparation of the desiredfinal compound,

one or more other substituents (or unsaturation) being introduced at alater stage. For example, it is possible for the preparation of ll-oxocompounds first to prepare an 11,8-hydroxy compound having the desired17a-acyloxy group and the desired 17B-carboxylate ester group and thenoxidise the 1118-hydroxy group. Other instances where the desiredsubstituents may be introduced before final elaboration of the remainderof the desired androstane molecule include for example preparing A901)or Ring A saturated compounds having the desired 17ccacyloxy and 173-carboxylate ester groups, completion of the elaboration of Rings A, Band C then being completed in conventional manner.

The elaboration of the characteristic l7-substitucnts of our newandrostane compounds may be conveniently effected from pregnanecompounds (having the following partial formula at the 17-position:

CHzOH by an oxidation in known manner to form a corresponding androstane17fi-carboxylic acid which acid may then be esterified. The 17a-hydroxygroup may be esterified or otherwise functionally converted prior tooxidation, and thereafter regenerated or converted, if desired, to adifferent l7a-3CY1OXY group.

The oxidative removal of the 21-carbon atom of the pregnane startingmaterial may be effected for example with periodic acid, in a solventmedium and preferably at room temperature. Alternatively, sodiumbismuthate may be employed to effect the desired oxidative removal ofthe 2l-carbon atom of a 17a-acyloxy pregnane compound.

As will be appreciated should the starting pregnane compound contain anysubstituent sensitive to the above- 6 described oxidation such groupshould be suitably protected.

The parent 17B-carboxylic acids of compounds of for mula I may beesterified in known manner to provide l7fl-carboxylate esters accordingto the invention. For example, in order to prepare a lower alkyl esterthe 17/3-carboxylic acid may be reacted with an appropriate diazoalkane,e.g. diazomethane, the reaction being preferably effected in a solventmedium, e.g. ether, tetrahydrofuran or methanol, and at a lowtemperature, preferably at 5 to +30 C. Alternatively, the 17B-carboxylicacid may be reacted with an appropriate O-alkyl-N,N-dicyclohexyl-isourea e.g. O-t-butyl-N,N -dicyclohexyl isourea,preferably in an aprotic solvent such as ethyl acetate, andadvantageously at a temperature of 25-100 C. Alternatively, a salt ofthe parent l7fi-carboxylic acid for example, an alkali metal e.g.lithium, sodium or potassium, salt or a quaternary ammonium, e.g.triethyl ammonium or tetrabutyl ammonium, salt may be reacted with andappropriate alkylating agent, for example, an alkyl halide e.g. theiodide or a dialkyl sulphate e.g. dimethylsulphate, preferably in apolar solvent medium such as acetone, methylethyl ketone or dimethylformamide, conveniently at a temperature in the range 25-100 C. Thereaction with an alkyl halide may conveniently be employed to preparethe ethyl and propyl 17B-carboxylate esters and higher alkyl estersaccording to the present invention.

Alternatively, the parent 17a-hydroxy-17fl-carboxylic acids of thecompounds of formula I may be esterified in known manner to provide thecorresponding 17a-hY- droxy-17/3-carboxylate esters. For example, the l73-carboxylic acid may be reacted with a diazoalkane or anO-alkyl-dicyclohexyl-isourea, or a salt of the l7fl-carboxylic acid maybe reacted with an alkylating agent as described above for thepreparation of the 17fl-carboxylate esters of the invention. Thel7a-hydroxy-17B-carboxylate esters may then be further esterified inknown manner to produce the compounds of the invention.

The esterification of the 17a-hydroxy group in the above-describedpreparation of the new androstane compounds may be eifected in knownmanner, e.g. by reacting the parent 17a-hydroxy compound with anappropriate carboxylic acid, advantageously in the presence oftriiiuoroacetic anhydride and preferably in the presence of an acidcatalyst, e.g. p-toluene-sulphonic acid or sulphosalicylic acid.

The reaction is advantageously effected in an organic solvent mediumsuch as benzene, methylene chloride or an excess of the carboxylic acidemployed, the reaction being conveniently effected at a temperature of20-100 C.

Alternatively, the 17a-hydroxy group may be esterified by reaction ofthe parent 17a-hydroxy compound with the appropriate acid anhydride oracid chloride, if desired, in the presence of non-hydroxylic solvents,e.g. chloroform, methylene chloride or benzene, and preferably in thepresence of a strong acid catalyst, e.g. perchloric acid, p-toluenesulphonic acid or a strongly acidic cation exchange resin, e.g.Amberlite IR 120, the reaction being conveniently eifected at atemperature of 25 to C.

For the preparation of the 17a-esters of the 17/3-carboxylic acids whichmay be employed in the preparation of the compounds according to theinvention, it is often preferred to treat the parent l7a-hydroxycompound with the appropriate carboxylic acid anhydride to give the17a-ester of the mixed anhydride of the androstane 17/3- carboxylic acidand the carboxylic acid of the starting anhydride, this reaction beingconveniently effected at an elevated temperature, the resultinganhydride then being solvolysed under acidic conditions (e.g. usingaqueous acetic acid) or under basic conditions (e.g. using aqueouspyridine or a secondary amine such as diethylamine in acetone).

Alternatively, the parent 17ahydroxy compound may be treated with theappropriate carboxylic acid chloride, preferably in a solvent such as anhalogenated hydrocarbon e.g. methylene chloride, and advantageously inthe presence of a base such as triethylamine, preferably at a lowtemperature e.g. C.

Compounds wherein the ll-position contains a keto group may be preparedfor example by oxidation of a corresponding 11,8-hydroxy compound, e.g.by means of chromium trioxide, conveniently in an inert solvent such asacetone, preferably in the presence of sulphuric acid. Alternatively,chromium trioxide in the presence of pyridine may be employed.

The above-described oxidation of an 11 fl-hydroxy group into an ll-ketogroup may be effected at any convenient stage in the synthesis of theandrostane compounds, e.g. prior to or after the oxidative removal ofthe 2l-carbon atom of the above-mentioned pregnane starting material orthe esterification of the 17a-hydroxy group.

Those compounds of formula I (wherein R represents a lower alkyl groupsubstituted by either at least one halogen atom or a loweralkoxycarbonyl group; or a lower (C alkyl group substituted by a loweracyloxy group) may be prepared for example by reacting a salt of theparent l7 8-carboxylic acid with an appropriate halo compound serving tointroduce the desired group R in the compound of formula I.

This reaction is advantageously effected using as the salt of the parent17,3-carboxylic acid an alkali metal e.g. lithium, sodium or potassium,salt or a quaternary ammonium salt such as the triethylammonium ortetrabutylammonium salt, conveniently in a polar solvent such asacetone, methylethyl ketone or dimethyl formamide.

If desired, the substituted lower alkyl groups represented by R, informula I may be suitably modified in conventional manner.

Thus, in the case when R; in formula I represents an alkyl groupsubstituted by a lower alkoxy-carbonyl group, the resulting compoundmay, if desired, be converted into a compound wherein R represents analkyl group with a difierent alkoxycarbonyl substituent by esterexchange e.g. by treatment with methanol in the presence of an acidcatalyst such as perchloric acid to convert an ethoxycarbonyl compoundinto the corresponding methoxycarbonyl compound.

In addition, the above-identified reaction of the salt of a17p-carboxylic acid with a halo compound may be used to preparecompounds of the type of formula I wherein R represents a lower alkylgroup containing at least two carbon atoms substituted by a hydroxygroup (in other than the tZ-pOSitlOH) which compounds may be convertedinto the corresponding halogen-substituted compounds via thecorresponding sulphonyloxyalkyl e.g. mesyloxyalkyl derivatives, suchconversion being carried out in conventional manner.

Thus, the sulphonyloxyalkyl compound may be advantageously reacted withan alkali metal, alkaline earth metal or quaternary ammonium halide,preferably lithium chloride, conveniently in a solvent mediumcomprising, for example, acetone, dimethyl formamide or ethanol.

Alternatively, the above-mentioned hydroxy-alkyl derivatives may beacylated e.g. with an appropriate carboxylic acid chloride or anhydrideto produce compounds of formula I according to the invention wherein Rrepresents a (C 4) alkyl group substituted by a lower acyloxy group.

Compounds of formula I wherein R represents a lower alkyl groupsubstituted by a halogen atom at the carbon atom attached to the oxygenatom of the l7fi-carboxylate may be prepared for example by reacting theparent 17,9- carboxylic acid with an appropriate aldehyde in thepresence of a hydrohalic acid. The reaction may advantageously beeffected in the presence of a catalyst for example, zinc chloride.

The A compounds according to the invention can conveniently be preparedby partial reduction of the: corresponding A compound, for example, byhydrogenation using a palladium catalyst, conveniently in a solvent e.g.ethyl acetate or by homogeneous hydrogenation using for exampletris(triphenyl phosphine) rhodium chloride, conveniently in a solventsuch as benzene, or by exchange hydrogenation using for examplecyclohexene in the presence of a palladium catalyst in a solvent e.g.ethanol, preferably under reflux.

It is to be noted that androstane compounds corresponding to our newclass of 17a-acyloxy compounds of the androstane series of formula I butcharacterised by a free hydroxy group at position 17 in the aconfiguration are new compounds apart from those compounds wherein X andR are both hydrogen, R is a methyl group, is a single bond and R is ap-hydroxy or oxo group. Such new compounds are useful intermediates forthe preparation of our new 17a-acyloxy compounds and constitute afurther feature of the invention.

Other novel androstane compounds of use as intermediates in thepreparation of the compounds of general formula I include the parent-carboxylic acids of such compounds and their anhydrides, e.g. theirmixed anhydrides with lower alkanoic acids, especially lower alkanoicacids such as acetic and propionic acids. Such 17fl-carboxylic acids andtheir anhydrides also constitute further features of the presentinvention.

For a better understanding of the invention, the following examples aregiven by way of illustration only.

In the following Examples Nos. 1-38, the preparation of the compounds isdescribed by reference to the following general methods of preparation Ato F given below, details of the compound prepared in each case and itsphysical constants being given in the subsequent tables.

Method A Preparation of androstane 17,8 carboxylic acids A solution ofthe 20-keto-2l-hydroxy pregnane steroid (1 part) in methanol (50 partsw./v.) was treated with a solution of periodic acid (1.5 parts w./w.) inwater (10 parts w./v.) at room temperature until the reaction was judgedcomplete (thin-layer chromatography). Most of the methanol wasevaporated and after addition of water the solid steroid l7fi-carboxylicacid was removed by filtration and purified by crystallization.

Method B Methylation of androstane 17fl-carboxylic acids.-The androstane17,8-carboxylic acid (1 part) was dissolved in methanol (6275 partsw./v.) and treated at 0 C. with an ethereal solution of diazomethaneuntil a yellow colour persisted and the reaction was shown to becomplete by thin-layer chromatography. After destruction of the excessdiazomethane with a few drops of acetic acid the reaction mixture wasevaporated to dryness in vacuo and the residue purified bycrystallization.

Method C PREPARATION OF C-l7 ESTERS BY ACYLA'I'ION OF 17aHYDROXYANDROSTANE-l7B-CARBOX- YLATES Method D p The 17a-hydroxy 175-carboxylate (1 part) was mixed with the appropriate aliphatic carboxylicacid (10 parts w./v.), trifluoracetic anhydride (1-2.4 nart w./v.) andtoluene-p-sulphonic acid (0.005-0.03 parts w./w. added as an anhydroussolution in chloroform) and the mixture heated in an oil bath at 80 C.until the reaction was judged, by thin-layer chromatography, to becomplete. The cooled reaction mixture was poured into excess diluteplete (t.l.c.). The mixture was poured into dilute sodium bicarbonatesolution and the precipitated product was removed by filtration, driedand recrystallized.

Method F sodlum 1 321 53 8 and i all P 5 Oxidation of llp-hydroxysteroids to 11-ketones.--'I11e cess y 1 e a een ecotflpose Preclpltatedllp-hydroxy steroid (1 part) was dissolved in acetone f f was removed byfiltratlon and Punfied by Y (25-150 parts w./v.), cooled in an ice-bathand a solution tallization. of chromium trioxide (prepared by addingconcentrated Method E sulphuric acid (53.3 ml.) to chromium trioxide(66.7 g.) h 1 h l in water and making the volume up to 250 ml. by addi-T W 2 8 (1 Part) the tion of water) (1.6-2.08 equivalents) was added.When P p aliphatic Q Y Q acld (about Parts the reaction was judgedcomplete (t.l.c.) the mixture was was treated with trifluoracetlc anhyParts diluted with ether or ether and ethyl acetate and washed andtoluenfi-p-slllphonlc (about 6 as an 15 thoroughly with water.Evaporation of the solvent atdrous solution in chloroform) and themixture kept at forded the crude ll-ketone which was purified bycrysroom temperature until the reaction was judged comtallization.

TABLE I General formula: C 01R o Example N 05. 1-17 Method FoundRequired oiprep- Cryst. M.P., [do Am, Empirical R R X aration solvent 0.(dioxan) nm. e formula H C H H H u.-H;B-OH A AP.E. 256-258 +62.5 23315,200 C21H2'1FO5 67.05 7.2 66.65 7.2 CH3 H 41-H;B-OH B AP.E. 241-243+71.6 239 15,100 02211261 05 67.3 7.5 67.35 7.45 02115 H a.-H;fl-OH 0AP.E 222-225 +68.6 236 15,200 024113.1 0. 67.3 7.3 67.95 7.7 C5H1u-H;B-OH 0 AP.E. 191-193 +57.2 233 15,100 OZJHIBFOB 68.2 3.0 7.9 CH3COCH; 5-11; 17-011 D 233-235 +36.6 236 16,200 CMHIHFOB 66.6 7.0 66.357.2 CH; 000.11. bum-0E D1 AP.E. 232-235 +352 238 15,400 CZSHSSFOQ 66.97.2 66.95 7,4 011. 000.111 a-H;BOH D A 238 15,700 04.11.5160. 67.6 7.567.5 7.6 02115 0001513 a-H;B-OH D3 AP.E 238 15,100 C25H33FO6 66.8 7.466.95 7.4 211. 0002115 u-H;B-OH D4 AP.E 236 15,300 C2UHE5FO6 67.4 7.567.5 7.6 02115 000311. 5-H; 151-011 D5 AP.E. 238 15,100 02.11.1101 67.47.5 68.05 7.85 03111 00011. a-H;fl-OH D AP.E 235 15,200 CZGHMFOQ 67.257.6 67.5 7.6 C3111 COCzHs a-H;B-OH D7 AP.E. 238 15,150 C27H31FO6 68-057.85 0.111 000.111 a-H; -011 D5 AP.E 238 15,300 CZBHSIFOU 68.6 3.0 68.556.4 CH3 00011. F A-RE 258-260 +7B.6 235 15,300 CZAHWFO 66.55 6.8 66.656.75 CH3 0002115 F AP.E. 228-230 235 ,600 C25H91FO6 67.6 7.1 67.25 7.0CH; 003111 F AP.E. 213-215 +69.9 235 14,100 02.11.11 0. 67.8 7. 5 67.87.2 0211. 0002B. F A-P.E. 183-185 235 14,700 01.61.5160 67.4 7 3 67.87.2

1 The reaction mixture was partly evaporated in vacuo before dilutionwith sodium bicarbonate solution. The crude product was filtered througha short column of grade III neutral alumina in chloroform beforecrystallizing.

5 A further quantity of trifluoracetic anhydride (0.5 parts w./v.) wasadded to the reaction mixture. 4 The crude product was extracted withethyl acetate and purified by preparative thinayer chromatography:

5 No toluene-p-sulphonic acid was added to the reaction mixture whichwas heated The crude product was purified by preparative thin-layerchromatography before crystallizing. 7 No toluene-p-sulphonic acid wasadded to the reaction mixture.

A =Acetone; P.E.=Petroleum-ether.

TAB LE II General formula: C 041R 0 R3 X "-CH6 Method 2 Found RequiredExample of prep- Cryst. M.P., [11]]; 1mm, Empirical number R 1 R 1 Xaration sovlent (dioxa nm. e formula C H C II 01-11; 5-0 H A 11-? .E 258+46. 6 238 15, 800 0 111117 F O 3 66. 6 7. 25 66. 65 7. 2 a-H; fl-O H Bl A-P .E 271-273 +38. 5 238 15, 200 C 22H70 F 05 67. 0 7. 3 67. 7. rx-H;fl-OH D AP.E. 316319 +11. 5 238 15, 700 CnHai F 0| 66. 45 7. 1 66. 35 7.2 a-H; fl-OH D 1 21-1 .E 230-233 +15 238 15, 000 CasHaa F O I 66. 7. 66.7. 4 02-11; fi-OH D a AP.E. 199-201 +14. 3 238 14, 700 CroHasF O. 67. 97. 65 67. 5 7. 65 =0 F .A-P.E. -188 +49. 2 235 CzsHai F 06 67. 1 6. 967. 25 7. 0

1 The crude product obtained by evaportation of the methanolic reactionmixture was dissolved in ethyl acetate and washed with dilute sodiumbicarbonate and water before crystallization.

2 The crude product was extracted with ethyl acetate and purifled bypreparative thin-layer chromatography. A=Acetone; P.E.=Petroleum-ether.Decomposition.

TABLE 111 General formula: I

X CHs /\l/\ F l 0 Method Found Required Ex. of prep- Cryst. M.P., [0111)Am Empirical No. R 1 R 1 X oration solvent C (dioxan) e formula. C H C H24.". H H a-H; fi-OH A A 236-238 -23. 4 238 15, 500 C2|H25F5 67. 1 6. 967. 0 6. 7 25..... OH; H a-H; B-OH B M 285-287 24. 5 238 15, 000C2H21F05 67. 5 7. 2 67. 7 6. 95 H a-H; BOH C M 258-261. 23. 2 238 15,410 CzzHzpFOa 68. 0 6. 9 68. 3 7. 25 COCHa a-H; ,B-OH D l M 254-258 -94.0 238 720 CflHggFO'e 66. 5 6. 9 66. 65 6. 75 COC H; a-H; fl-OH D 2 M198-200 -97. 5 238 15, 200 CH 1FOe 67. 1 7. l 67. 25 7. 0 6003117 a-H;B-OH D 1 M 189-192 86. 5 238 15, 580 CzaHasFOo 67. 4 7. 4 67. 8 7. 2COCH(CH a-H; B-OH D 3 M 185487 -84. 0 238 15, 580 Oral-IggFOo 67. 8 7. 467. 8 7. 2 COCH; a-H; B-OH D M 278280 99. 0 238 15,300 C zsHaiFOe 67. 16. 9 67. 25 7. 0 COCzHs a-H; B-OH D 3 M 195-197 -85. 1 238 15,800 CggHgFOa 67. 7 7. 2 67. 8 7. 2 COCH(CH:)2 u- B-0H D i EtOAc 145-148 79. 523B 15, 600 027E350; 68. 6 7. 2 68. 7. 45 OOCH; =0 F 229-232 42. 7 23515, 390 C24H27F0u 66. 8 6. 3 66. 95 6. 3

i The crude product was purified by preparative thin-layer chromatog- IThe crude product was extracted with ethyl acetate. raphy beforecrystallizing. "A =Acetone; M=Methanoh 1 The crude product was extractedinto ethyl acetaie and purified by preparative thin-layer chromatographybefore crystallizing.

TABLE IV General formula:

Method Found Required oi prep- Empirical E xample number B R arationCryst. solvent e formula C H C H H A l A-EtOH-RE. 14, 300 (3211511001204I 6. 10 6. 3 61.0 6. 35 H B I .AP.E. 1-1, 500 012112501204 4 61. 8 6. 661.85 6. 6 COCH; E 11-11 13, 960 024113001305 61. 2 6. 4 61. 4 6. 45COCzHs E A-H 14, 100 CarHmChOs 6. 20 6. 6 62. 1 6. 65

l 120 parts (w.lv.) of methanol was used and a little dloxan added toaid dissolution of the steroid.

1 Found: Cl, 17.2. Required, Cl, 17.27

The crude product from evaporatiori of the methanol was dissolved inchloroform and filtered through a short plug of neutral grade IIIalumina before crystallization.

4 Found: Cl, 16.8. Required, 01, 16.6%. A=Aoetone;P.E.=Petroleu.m-ether; H=Hexane.

EXAMPLE 39 Methyl iodide (12 ml.) was added to a solution of 9mfluoro-llfl,17a-dihydroxy-l65-methyl 3 oxo-androsta-1,4-dicnc-17fi-carboxylic acid (10.045 g.) in acetone (500 ml.)containing tricthylamine (4.6 ml.) and the mixture refluxed, more methyliodide (6 ml.) being added after 4 hours. After 5.25 hours most of thesolvent was evaporated in vacuo and the residue diluted with sodiumbicarbonate solution. The precipitated solid was removed by filtrationand, after drying, was filtered through a short plug of grade (III)neutral alumina in ethyl acetate containing a little methanol.Evaporation of the eluate gave methyl9a-lluoro-11B,17u-dihydroxy-i6B-mcthyl-3-oxo-androsta-1,4-dicne-17fl-carboxylate with infrared and N.M.R. spectraresembling that of the methyl ester prepared with diazomcthane.

- EXAMPLE 40 androsla-l,4-dienc-l7fl-carboxylic acetic anhydride 9ozFluoro-l1p,l7a-dihydroxy-lofi-mcthyl 3 0x0-androsta-l,4-diene-17B-carboxylic acid (1 g.) was suspended in aceticanhydride (15 ml.) and heated on a steam-bath for minutes and then at115 for 1 hour by which time all the steroid had dissolved. The mixturewas cooled and the precipitated material removed by filtration andrecrystallized from acetone-hexane to aiford17a-acetoxy-9a-fluoro-llfi-hydroxy 166methyl-3-oxoandrosta-1,4-diene-l7fl-carboxylic acetic anhydride, m.p.218-220", [11],; +42.4 (c 0.8, dioxan), A 238 nm. (a 15,900). (Found: C,64.65; H, 6.5. C25H31FO1 requires C, 64.9; H, 6.75%.)

EXAMPLE 41 (1) 17oz-ACCtOXy-9a-fll101'0-1 lfi-hydroxy 16B- methyl-3-oxoandrosta-1,4-diene-l7B-carboxylic acetic anhydride (530 mg.) wasdissolved in acetic acid ml.) and water (50 ml.) added and the mixturekept at room temperature until reaction was complete (45 minutes).Evaporation in vacuo afforded the product which, after crystallizationfrom acetone-petroleum ether gave acetoxy-Qu-fiuoro 11B hydroxy 166methyl-3-oxoandrosta-l,4-diene-l7fl-carboxylic acid, m.p. 2122l4, [111+222 (c 0.8, dioxan), k 239 nm. (5 14,700). (Found: C, 64.1; H, 7.1.C23H29F06 requires C, 64.3; H, 7.05%.)

(2) l7-a-Acetoxy-9u-fiuoro-1lfi-hydroxy 16B methyl-3-oxoandrosta-1,4-dienc-17B-carboxylic acetic anhydride (57 mg.) wasdissolved in 50% aqueous pyridine (8 ml.) and kept at room temperaturefor 45 minutes. Evaporation of the solvent gave a solid whose infraredand N.M.R.

13 spectra were similar to those of the material prepared in (1) above.

EXAMPLE 42 9oz Fluoro 11 8hydroxy-16fl-methyl-3-oxo-17m-propionyloxyandrosta-1,4-diene 17,8carboxylic propionic anhydride EXAMPLE 43 9u-Fluoro-11fl-hydroxy-l6fi-methyl-3-oxo-17u-propionyloxyandrosta-1,4-diene-17B-carboxylicacid (1) 9a-Fluoro-11B-hydroxy 16Bmethyl-3-oxo-17apropionyloxyandrosta-1,4-diene-17B-carboxylic propionicanhydride (342 mg.) was dissolved in acetic acid (25 m1.) and water (15ml.) added and the mixture kept at room temperature until the reactionwas judged complete (t.l.c.). Evaporation in vacuo of most of thesolvent and dilution with water afiorded the product which wasrecrystallized from acetone-hexane to give 9a-fluoro-11B-hydroxy-16fl-methyl 3 oxo 17apropionyloxyandrosta-1,4-diene-17B-carboxylic acid, m.p. 188-190", k 239nm. (6 15,600). (Found: C, 65.1; H, 7.5. C H FO -Me CO requires C, 65.8;H, 7.6%.)

(2) 9u-Fluoro-11fi-hydroxy 1618methyl-3-oxo-17upropionyloxyandrosta-1,4-diene-17B-carboxylic propionicanhydride (6.93 g.) in acetone (150 ml.) was treated with diethylamine(5 ml.) and the mixture kept at room temperature for about 0.5 hours.The solvent was evaporated in vacuo and the residue was dissolved inwater, acidified and extracted with ethyl acetate. The washed organiclayer was evaporated in vacuo to give a solid which was triturated withether to give 9a-fluoro-11B- hydroxy-16fl-methyl 30x0-17u-propionyloxyandrosta- 1,4-diene-17B-carboxylic acid.

EXAMPLE 44 Methyl 9a fluoro 16methylene-3,11-dioxo-17apropionyloxy-androsta-1,4-diene-17,8-carboxylateMethyl 9oz fluoro 1lfl-hydroxy-16-methylene-3-oxo-17a-propionyloxylandrosta 1, 4- diene 17fi-carboxylate .(204 mg.) inacetone (4 ml.) was treated at room temperature with a solution ofchromium trioxide [0.23 ml.; prepared by adding concentrated sulphuricacid (53.3 ml.) to chromium trioxide (66.7 g.) in water and making thevolume up to 250 ml. with water]. After 30 minutes the reaction mixturewas diluted with ether and washed successively with water, sodiumbicarbonate solution and water. The dried ethereal solution wasevaporated in vacuo and the residue was recrystallised from methanol toafford the title compound, m.p. 194-195 [041 37.8 (c 1.06, dioxan), x234.5 nm. (2 15,800). (Found: C, 67.3; H, 6.7. 0 1-1 1 0 requires C,67.55; H, 6.58%.)

EXAMPLE 45 Methyl 17 a-benzoy1oxy-9a-fluoro-11B-hydroxy-16flmethyl-3-oxo-androsta-1,4-diene-17fi-carboxylate Asuspension of methyl 9a fiuoro-11fl,17a-dihydroxyl6fi-methylandrosta 1,4diene 17fi-carboxylate (439 mg.) in methylene chloride (15 ml.) wastreated with benzoic acid (573 mg.), trifluoroacetic anhydride (0.6 m1.)and toluene-p-sulphonie acid (12 mg.) and the mixture was stirred atAfter 48 hours the mixture was cooled and diluted with methylenechloride and the solution was washed with sodium bicarbonate and water.Evaporation of the dried organic solution atforded a residue which waspurified by preparative thin layer chromatography and crystallisationfrom methanol to give the title benzoate, m.p. 166-168, [061D 33 (01.09, dioxan), A 232 nm. (6 27,800). (Found: C, 70.0; H, 6.6. C H FOrequires C, 70.14; H, 6.7%.)

EXAMPLE 46 Methyl 9a-fiuoro-1lfl-hydroxy-16B-methyl-3-oxo-17b:-propionyloxy-androst-4-ene-17B-carboxylate A solution of methyl 9ozfluoro 11,3-hydroxy-16flmethyl 30x0-l7a-propionyloxyandrosta-1,4-diene-17flcarboxylate (454 mg.) inethanol (45 ml.) was treated with 5% palladium-charcoal (453 mg.) andcyclohexene (0.9 ml.) and the mixture was refluxed for 15 minutes.Filtration of the cooled mixture and evaporation of the solvent in vacuoafforded a froth which, after purification by preparative thin layerchromatography and crystallisation from acetone-petroleum ether gave thetitle compound, m.p. 204-208, 8 237.5 nm. (6 15,400). (Found: C, 66.8;H, 7.8. C H F0 requires C, 66.65; H, 7.8%.)

EXAMPLE 47 Methyl 9a-fluoro-16fi-methyl-3, 11-dioxo-17a-propionyloxyandrost-4-ene-17,8-carboxylate A solution ofmethyl 9a fluoro 11 8-hydroxy-l6flmethyl-3-oxo-17a-propionyloxyandrost 4ene-17/3-carboxylate mg.) in acetone (7 ml.) was treated, at 0", with asolution of chromium trioxide [0.09 ml.; prepared by adding concentratedsulphuric acid (53.3 ml.) to chromium trioxide (66.7 g.) in water andmaking the volume up to 250 ml. with water]. After 1.25 hours themixture was diluted with ether and ethyl acetate and washed thoroughlywith water. Evaporation of the organic solvent then alforded a whitesolid which was crystallised from acetone-petroleum ether to give thetitle compound, m.p. 218-220 after previous softening, Amax, 234 nm. (e16,000). (Found: C, 66.55; H, 7.4. C H FO requires C, 66.95; H, 7.4%.)

EXAMPLE 48 Methyl 17a-acetoXy-l 1{3-hydroxy-3-oxoandrosta-1,4-

diene-17fi-carboxylate Periodic acid (14.163 g.) in water (80 ml.) wasadded to a solution of prednisolone (8.286 g.) in methanol (800 ml.) andthe resulting mixture was kept at room temperature. After 1 hour most ofthe methanol was evaporated in vacuo, the residue was diluted withwater, and the crystalline 11 8,17a dihydroxy 3 oxoandrosta- 1,4 diene17,3 carboxylic acid removed by filtration. The analytical sample whichwas crystallized from wet acetone and petroleum ether had m.p. 264266.(Found: C, 69.2; H, 7.4. C H O requires C, 69.3; H, 7.5%.)

The above carboxylic acid (3.6 g.) in methanol (200 ml.) was treated at0 with an ethereal solution of diazomethane until the mixture wasyellow. Evaporation of most of the organic solvent in vacuo and dilutionof the residue with water afforded crystalline methyl 113,170:-dihydroxy 3 oxoandrosta 1,4-diene-17fi-carboxylate, m.p. 203-206. Asample crystallised from acetonehexane had m.p. 202205, [a] +59.6 (c 0.8dioxan), A 242.5 nm. (6 15,100). (Found: C, 70.0; H, 7.9. C H O requiresC, 69.98; H, 7.83%.)

The above methyl ester (464 mg.) in acetic acid (5 ml.) was treated withtrifluoroacetic anhydride (1 ml.) and the mixture stirred at roomtemperature. After 1 hour toluene p sulphonic acid (7 mg.) was added andthe mixture kept at room temperature for a further 2.5 hours. Dilutionof the solution with sodium bicarbonate solution afforded a precipitatewhich was removed by filtration and purified by preparative thin-layerchroma- 15 tography and crystallization to yield the title compound, mp.284-286", [d +8.9 (c 0.7 dioxan), )t 243 nm. (6 FQUIldI C, H, C23H3006requires C 68.65; H, 7.5%.)

EXAMPLE 49 Methyl 9ct-fiuoro-1 15,17a-dihydroxy-l6fl-methyl-3oxoandrosta-1,4-diene-17fi-carboxylate EXAMPLE 502'Hydroxyethyl-9a-fluoro-11B-methyl-3-oxo-17'm-propionyloxyandrosta-1,4-diene-175-carboxylateEXAMPLE 51 2-Methanesulphonyloxyethyl 9a-fluoro 11,8 hydroxy16fl-rnethyl-3 oxo 17a propionyloxyandros-ta 1,4- diene-l7p-carboxylateA solution of 2'-hydroxyethyl 9afiuoro-11fl-hydroxy-16B-methyl-3-oxo-17a-propiony1oxyandrosta 1,4 diene- 17fl-carboxylate(240 mg.) in dry pyridine (1 ml.) was treated dropwise at 1 to withredistilled methanesulphonyl chloride (0.2 ml.). After 40 minutes themixture was poured into 2N-sulphuric acid (8 ml.) and triturated to givea solid which was purified by preparative thin-layer chromatography andrecrystallisation from methanol to give the title compound, m.p.129-131", A

238 nm. (e 15,850). (Found: C, 58.5; H, 6.7. C H FO 'S requires C, 58.3;H, 6.7%.)

EXAMPLE 52 2'-Chloroethyl 9oc-fluoro-11B-hydroxy-16B-methyl-3-oxol7a-propionyloxyandrosta-1,4-diene-17fi-carboxylateA mixture of 2'-methanesulfonyloxyethyl 9lX-fiuOI'O- llfl-hydroxy16B-methyl 3 oxo 17o: propionyloxyandrosta-1,4-diene-175-carboxylate(223 mg.) and dry lithium chloride (170 mg.) on acetone (9 ml.) wasrefluxed for 22 hours. After removal of solvent in vacuo the residue wastriturated with water to give a solid which was purified by preparativethin-layer chromatography and crystallisation from ether to afford thetitle chloroethyl ester, m.-p. 194-196 [u] +43.'4 (c 0.99, dioxan), A237 nm. (E 15,800). (Found: C, 62.9: H, 6.9; Cl, 7.0. C H CIFO requiresC, 62. 8; H, 6.9; Cl, 7.1%.)

EXAMPLE 53 2'-Bromoe-thyl Qua-11110104 lp-hydroxylfifi-methyl-S-oxo- 17e-propionyloxyandrosta-1,4-diene- 17 B-carboxylate Treatment of2'-methanesulphonyloxyethyl S ot-fluorollfi-hydroxy ldfi-methyl 3 oxo17a propionyloxyandrosta-l,4-diene-17B-c'arboxylate (22-2 mg.) with drylithium bromide (348 mg.) in acetone (9 ml.) for 2 hours followed bywork-up as described in Example 52, with purification from etherafforded the title bromoethy-l ester, m.p. 182-1845, softening above122, [a1 +3818 (c 1.02, dioxan), Amax, 237.5 nm. (6 16,000). (*Found: C,57.9; H, 6.3; Br, 14.6. c,,H,,BrFo, requires C, 57.7; H, 6.3; Br,14.8%.)

EXAMPLE 54 Qa-ChlOIO-l 1p,17a-dihydroxy-16fi-methyl-3-oxoandrosta-1,4-diene-17fi-carboxylic acid Treatment of 9a-chloro-1l5,17a-21trihydroxy 16cmethylpregna-l,4-diene-3,20-dione by the proceduredescribed in Method A afforded, after recrystallisation fromacetone-ethanol-petrol the title carboxylic acid, mp. 247- 249", [ad+93.0 (c 0.7, dioxan), A 238.5 nm. (5 14,300). ('Found: C, 63.3; H, 7.1.C H CIOL; requires C, 63.85, H, 6.9%.)

EXAMPLE 55 Qcz-ChIOI'O-l lfi-hydroxy- 16;8-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17B-carboxylic acid A mixture of9a-chloro-11,8,17a-d'ihydroxy-lfifl-methyl-3-oxoandrosta-1,4-diene-l7fl-carboxylic acid (1.42 g.) (35 ml.) wasstirred at 0 and treated dropwise with propionyl chloride (1.32 ml.).After 35 minutes at 0 the solution was diluted with methylene chloride,washed successively with 3% sodium bicarbonate solution, N-hydrochloricacid and water; after being dried (magnesium sulphate) solvent wasremoved in vacuo to give a colourless crystalline solid. This solid wasdissolved in acetone (40 ml.) and treated with red istilled diethylamine(1.3 ml.); concentration in vacuo gave the crystalline diethylamine saltwhich was collected, dried, dissolved in water and the solution wasacidified with ZN-hydrochloric acid. The product was extracted withethyl acetate and solvent was removed to give crystalline9a-chloro-l1fi-hydroxy- 16fl-methyl 3-oxo-17u-propionyloxyandrosta 1,4dienel7fi-c-arboxylic acid (1.49 g.), m.p. 18718'8 (decomp.), [e1 +5210(C 0.95, dioxan), A 238 nm.

EXAMPLE 5 6 Methyl 9a-chloro- 1 1 fi-hydroxy-l 6;.9-methyl-3-oxo-17apropionyloxy androsta- 1,4-diene- 17 fi-carb oxyl-ate A solution of9a-chloro-1lfl-hydroxy-l6fi-methyl-3-oxo-17a-pr0pionyloxyandrosta-1,4-diene-l7fi earboxylic acid (501 mg.) inacetone (20 ml.) was cooled in ice and treated with an ethereal solutionof diazomethane according to Method B. After being subjected tochromatography on silica the product was recrystallised from methanol togive the title methyl ester, m.p. 214-217 (decomp.), [@1 +603 (0 0.97,dioxan), A 237 nm. (e 15,700). (Found: C, 64.5; H, 7.2; Cl, 7.5. C 5HClO requires C, 64.6; H, 7.15; CI, 7.6%.)

EXAMPLE 57 1 1B, 17a-Dihydroxy-16,8-methyl-3-oxoandrosta-1,4-diene-17B-carboxylic acid A solution of11e,17u,2l-trihydroxy-16fl-methylpregna- 1,4-diene-3,20-dione (640 mg.)in dioxan (28 ml.) was stirred and treated with a solution of periodicacid (1.76 g.) in water (14 ml.). After 40 minutes the solution wasdiluted with water (14 ml.) and concentrated in vacuo. The crystallineproduct (579 mg.) was recrystallised from acetone to give the titleacid, m.p. 226-229 (decomp.), [a1 +78.0 (c 0.50, dimethylsulphoxide), k242 nm. (6 14,850). (Found: C, 70.1; H, 8.0. C H O requires C, 70.0;1-1,7.8%.)

1 7 EXAMPLE 58 1 1 fl-Hydroxy- 16,3-methyl-3 -oxo-17a-propionyloxyandrosta-1,4-diene-17B-carboxylic acid Treatment of11,3,l7a-dihydroxy-16fl-methyl-3-oxoandrosta-1,4-diene-175-carboxylicacid (310 mg.) with propionyl chloride (0.269 ml.) followed bysolvolysis of the resulting product with diethylamine by the methoddescribed in Example 55 aflorded crystalline llfi-hydroxy- 16fl-methyl 3oxo-l7a-propionyloxyandrosta-1,4-dienel7B-carboxylic acid, m.p. 202-205(decomp.), [11] +24.4 (c 0.97, dioxan), A 242.5 nm. (6 14,820).

EXAMPLE 5 9 Methyl 11fl-hydroxy-16i3-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17/3-carboxylateEXAMPLE 60 t-Butyl 9u-fluoro- 1 1B-hydroxy-16/3-methyl-3-OX-17apropionyloxyandrosta-1,4-diene-17fi-carboxy1ate A suspension of9a-fluoro-11 3-hydroXy-16p-methyl-3-oXo-17apropionyloxyandrosta-1,4-diene-17,3 carboxylic acid (400 mg.) inethyl acetate ml.) was treated with O-t-butyl-N,N'-dicyclohexylisourea(1.14 g.) and the mixture was refluxed for hours. 2N-Hydrochloric acidwas added and the mixture was stirred thoroughly; solid material wasremoved and washed thoroughly with ethyl acetate and water. The combinedethyl acetate solutions were washed with saturated sodium bicarbonatesolution, and water, dried over magnesium sulphate and solvent wasremoved in vacuo. The resulting product (398 mg.) was purified bychromatography on silica and crystallised first from acetone-petrol thenfrom methanol to give the title t-butyl ester, m.p. 200207, [@1 +352. (00.95, dioxan), A 238-2385 nm. (e 14,600). (Found: C, 68.8; H, 8.1. C l-11 0 requires C, 68.55; H, 8.0%.)

EXAMPLE 61 17a-Butyryloxy-1 1B-hydroxy-3-oxoandrost-4-ene-17B-carboxylic acid 11 9,171: Dihydroxy-3-oXoandrost-4-ene-l7p-carboxylicacid (1.5 g.) was treated with n-butyryl chloride (3.0 ml.) and theproduct was solvolysed with diethylamine by the method described inExample 55 to give, after recrystallisation from methanol,l7a-butyryloxy-11B-hydroxy-3- oxoandrost-4-ene-17B-carboxylic acid, m.p.222-223 (decomp.), [111 +45.1 (c 0.98, dioxan), a 240 nm. (6 16,300).(Found: C, 68.3; H, 8.2. C H O requires C, 68.9; H, 8.2%.)

18 EXAMPLE 63 Methyl abutyryloxy-l1fl-hydroxy-3-oxoandr0st-4-enel7fi-carboxylate Treatment of170: butyryloxy 11 3 hydroxy-3-oxoandrost-4-ene-17fi-carboxylic acid(400 mg.) in methanol (40 ml.) with ethereal diazomethane according toMethod B gave, after recrystallisation from methanol, the little methylester, m.p. 162-165", [a] +49.4 (c 0.71, dioxan), a 240 nm. (5 16,550).(Found: C, 69.05; H, 8.3. C H O requires C, 69.4; H, 8.4%.)

EXAMPLE 64 1 1 fl-Hydroxy-3 -oxo- 17 a-propionyloxyandro st-4-ene- 1718-carboxylic acid Treatment of 11;8,17u dihydroxy 4 3-oxoandrost-4-ene-17fl -carboxylic acid (3.0 g.) with propionyl chloride (2.7 ml.) andsolvoylsis of the product with diethylamine (3.25 ml.) by the methoddescribed in Example 55 afforded, after recrystallisation fromacetone-petrol, 11B- hydroxy 3oxo-17a-propionyloxyandrost-4-ene-17B-carboxylic acid, m.p. 225-226(decomp.), [ab +462 (0 0.98, dioxan), A 240.5 nm. (e 15,500). (Found: C,67.1; H, 7.8. C H O /zH O requires C, 66. 8; H, 7.8%.)

EXAMPLE 65 Methyl 1 1/8-hydroXy-3-oxo-17a-propionyloxyandrost-4cne-17fl-carboxylate Treatment of 11,8-hydroXy-3-oxo-17upropionyloxyandrost-4-ene-17/3-carboxy1ic acid (2.5 g.) in methanol,(400 ml.) with ethereal diazomethane according to Method B gave a crudeproduct; chromatography of a portion on silica afforded, afterrecrystallisation from methanol, the title methyl ester, m.p. 176-178",[uh +51.1 (c 0.59, dioxan), A 240 nm. (5 15,800). (Found: C, 68.9; H,8.3. 'C H O requires C, 68.9; H, 8.2%.)

EXAMPLE 66 17 a-Acetoxy- 1 1p-hydroxy-3-oxoandrost-4-ene-17B- carboxylicacid Reaction of l1B,17a-dihydroxy-3-oxoandrost-4-ene-17B- carboxylicacid (3.0 g.) with acetyl chloride (2.2 ml.) and solvolysis of theproduct with diethylamine (3.0 ml.) by the method described in Example55 gave, after chromatography on silica and recrystallisation fromacetonepetrol, the title l7p-carboxylic acid, m.p. 161-167, [a1 +42.8 (c0.25, dioxan), A 241 nm. (6 14,550). (Found: C, 64.6; H, 7.5. C H O-requires C, 64.7; H, 7.9%.)

EXAMPLE 67 Methyl 17oc-acetoxy-11p-hydroxy-3-oxoandrost-4-ene-17fl-carboxylate Reaction of 17a-acetoxy-11fl-hydroXy-3-oxoandrost-4-ene-17fl-carboxylic acid (2.3 g.) in methanol (368 ml.) with etherealdiazomethane according to Method B gave, after recrystallisation fromethanol, the title methyl ester, m.p. 250-252", [a] =+54.5 (c 0.61,dioxan), A 240 nm. (e 15,350). (Found: C, 67.9; H, 8.0. C H O requiresC, 68.3; H, 8.0%.)

EXAMPLE 68 2Acetoxyethyl 9a-fil10fO-1 1fl-hydroxy-16p-methyl-3 -oxo-17a-propionyloxyandrosta-1,4-diene-17fi-carboxylate A solution of2'-hydroxyethyl 9a-fiuoro-11p-hydroxy- 16/3-methyl-3-oxo-17apropionyloxyandrosta-1,4 dienel7p-carboxylate (300 mg.) in dry pyridine(6 ml.) was treated with acetic anhydride (0.6 ml.). After being kept atroom temperature for 2% hours the mixture was poured into well-stirredN-sulphuric acid to give a colourless solid (311 mg.) which was purifiedby preparative thin-layer chromatography on silica. Tworecrystallisations from acetone aiforded colourless crystals of the 19title acetoxyethyl ester, mp. 156-158", [111 +319 (c 0.98, dioxan), A237 nm. (as 15,800). (Found: C, 64.6;

Ball-mill the steroid with a little of the liquid paraffin until theparticle size is reduced to 95% by number below pc. Dilute the paste andrinse out the mill with the remaining liquid parafiin, mix and add thesuspension to the melted white soft paraffin at 50 C. Stir until cold togive a homogeneous ointment.

EXAMPLE (b) Percent w./w. Active ingredient 0.25 Aluminium stearate 3.2Liquid parafiin B.P. to 100 parts.

Disperse the aluminium stearate in the liquid parafiin by vortexstirring and heat the suspension with continued stirring, at atemperature rise rate of 2 C. per minute until 90 C. is reached.Maintain the temperature at 90- 95 C. for 30 minutes until solution iscomplete and a gel is formed. Cool quickly, preferably by the use ofcooling coils or concentric cooling rings to produce a transparent solidgel. Mill the active ingredient to produce microfine particles of whichnot less than 90% by number are below 5 Triturate with a small portionof the gel and incorporate the remaining gel to give a homogeneous mix.

EXAMPLE (c) Percent w./w. Active ingredient 0.1 Woolfat 12.0 Cetostearylalcohol B.P.C. 20.0 Liquid paraffin B.P. 25.0 White soft paraffin to 100parts w. /w.

Ball-mill the steroid with a little of the liquid parafiin as in Example(a) and add the resulting paste, diluted with the remaining liquidparaflin, to a mixture of cetostearyl alcohol, woolfat and white softparatiin, melted together White soft paraffin to 100 parts w./w.

Ball-mill the steroid with liquid paraffin as in Example (a), and addthe resulting paste, diluted with the remain: ing liquid paraflin to themixture of hydrogenated lanolin and white soft parafiin melted togetherby gently warming. Stir until cold to give a homogeneous mix.

The following examples (e) and (f) illustrate the preparation ofwater-miscible creams: I,

EXAMPLE (e) Percent w./w. Active ingredient 0.1

Beeswax (White) ..V.. 15.0 Cetostearyl alcohol B.P.C. 7.0 Cetomacrogel1000 B.P.C. 3.0 Liquid parafiin B.P. 5.0 Chlorocresol 0.1 Distilledwater to produce 100 parts by weight.

Ball-mill the steroid with a little liquid parafiin as described inExample (a). Heat the available water to 100 C., add the chlorocresol,stir to dissolve and cool to 65 C. Melt together the beeswax,cetostearyl alcohol and cetornacrogel and maintainat 65 C. Add thesteroid suspension using the remaining liquid paraffin for rinsing. Addthe steroid oil phase at 60 C. to the chlorocresol aqueous phase at 65C. and stir rapidly while the emulsion cools over the gelling point(4045 0.). Continue to stir at slow speed until the cream sets.

EXAMPLE (r Percent w./w.

Active ingredient 0.1 Cetostearyl alcohol B.P.C. 7.2 'Cetomacrogel 1000B.P.C. 1.8 Liquid paraffin B.P. 6.0 White soft parafiin 15.0Chlorocresol 0.1

Distilled water to produce 100 parts by weight.

Prepare as described in Example (e), replacing the beeswax with whitesoft paraflin in the oily phase.

The following examples (g) and (h) illustrate the preparation oflotions:

EXAMPLE (g) Percent w./w.

Active ingredient 0.25 Lanbritol wax 0.93 Diethylene glycol monostearate0.65 Cetostearyl alcohol B.P.C. 0.65 Liquid parafiin B.P. 1.95 Glycerin5.0 Isopropyl alcohol 6.5 Methyl p-hydroxy benzoate 0.15

Distilled water to produce 100vo1umes.

Lanloritol wax is a non-ionic wax for stablisliing emulsions consistingof a mixture of fatty alcohols with polyethylene glyeol ethers of fattyalcohols sold by Ronshelm Moore of London W. G. 1, England.

Ball-mill the steroid with half the glycerin, as in EX- ample (a), anduse the isopropyl alchol for dilution and rinsing purposes.

Melt together the lanbritol Wax, diethylene glycol monostearate,cetostearyl alcohol and liquid paraflin and maintain at 60 C. Heat theavailable water and remaining glycerin to C. Add the methyl p-arahydroxybenzoate and stir until dissolved. Cool to 65 C. Add the oily mix at 60C. to the aqueous phase at 65 C. and allow to cool while stirringrapidly until the emulsion gels at 40-45 C., there-after stir slowly.Add the well mixed steroid suspension slowly to the lotion base and stirto obtain a homogeneous mix. 1

EXAMPLE (h) Percent w./v.

Active ingredient 0.05 Tween 80 (polyoxyethylene sorbitan monooleate)0.01 Carbopol 934 (carboxy vinyl polymers) 0.3 Diethanolam'ine 1 0.5Distilled water to produce volumes.

1 Approximately.

' Ball-mill the steroid with a little water and the Tween 80 as inExample (a). Disperse the Carbopol 934 in the available water by vortexstirring. Add the diethanolamine slowly with stirring until the clearthickened mix has a pH of 7.0. Incorporate the steroid slurry into thelotion base and mix well.

21 EXAMPLE (i) Aerosol Spray Lotion Active ingredient (microfine) mgm2.5 Fractionated coconut oil to 1.20 g. Dich'lorodifiuoromethane g 16.32Trichlorofiuoromethane -g 24.48

' Dry the steroid overnight at 60 C. under vacuum and over phosphoruspentoxide. Ball-mix the dried powder for at least 4 hours with a littleof the dried filtered oil. Rinse out the'mill with more dried filteredoil and pass the suspension through a 325 mesh B.S. sieve. Assay thesuspension and dilute with more dried filtered oil to the requiredconcentration. Incorporate the suspension into the pressure containerwith the propellants in a conventional manner.

EXAMPLE (j)- Aphthous Ulcer Pellets Mg. Active ingredient (microfine)0.25 Lactose 69.90

Acacia 3.00 Magnesium stearate 0.75

Pass thesteroid, lactose and acacia, separately through a N0. 60 BS.mesh sieve. Blend the powders and granulate with 50% ethanol in water.Pass the mass through a No. 12 mesh sieve and dry the granules at 50 C.Pass the dried granules through a No. 20 mesh B.S. sieve and blend inthe magnesium stearate, previously passed through a No. 100 mesh B.S.sieve. Compress in a conventional manner on 7 inch diameter punches, togive a pellet that will dissolve slowly in the mouth.

EXAMPLE (k) Retention Enema Active ingredient (microfine) percent w./v0.0005 Tween 80 do 0.05 Ethanol percent v./v 0.015 Methyl p-hydroxybenzoate percent w./v 0.08 Propyl p-hydroxy benzoate do 0.02 Distilledwater to 100 vols.

Heat the available water to 95 (3., add the methyl and propyl p-hydroxybenzoates and stir to dissolve. Cool the vehicle to room temperature.Disperse the steroid in the ethanol and add to the Tween 80; warm themixture to 50", C. and stir until the steroid is in solution. Add thesteroid solution to the vehicle, stirring vigorously to avoidprecipitation, and make up to volume with water if required. Distributethe enema into plastic bags e.g. P.V.C. bags for self-administration orinto other containers suit- Water for injection to 100 volumes.

Dissolve the sodium chloride, benzalkonium chloride and phenyl ethanolin the water for injection. Suspend the steroid in the alcohol and addto the Tween 80. Warm the mixture to 50 C. and stir until dissolved. Addthe steroid solution to the eye-drop vehicle with rapid stirring toobtain a clear solution. Sterilise the bulk by filtration through asintered glass filter and distribute into sterile small well filled,neutral glass eye-drop containers.

22 EXAMPLE (m) Nasal Drops Active ingredient percent w./v 0.005 Tween do0.05 Alcohol percent v./v 0.15 Methyl paraben (p-hydroxy benzoate)percent w./v 0.04 Propyl paraben (p-hydroxy benzoate) do 0.02 Sodiumchloride d0.. 0.70

Distilled Water to volumes.

Dissolve the sodium chloride and the parabens in the distilled waterheated to 95 C., and allow the solution to cool. Disperse the steroid inthe alcohol and add to the Tween 80. Warm the mixture to 50 C. and stiruntil solution of the steroid is effected. Add the steroid solution tothe vehicle with rapid stirring to obtain a clear solution. Filter thesolution free from particulate matter through a sintered glass filterand distribute into small, well filled containers.

The following Examples (n) and (0) illustrate formulations for internaladministration according to the invention. In both examples the activeingredient used may be any of the active steroid hereinbefore disclosed.

EXAMPLE (11) Oral Tablet Active ingredient 0.5 Lactose 175.5 Maizestarch (dried) 20.0 Gelatin 2.0 Magnesium stearate 2.0

Total weight 200.0

A suspension of 360 mg. of the active ingredient in 2 ml. of watercontaining 0.1% of Tween 80 was milled for 16 hours in a 10 ml. nylonpot about three quarters filled with steatite balls, until 90% by numberof the particles had a diameter of less than 10 microns. The maizestarch and lactose Were blended and passed through a 60 mesh B.S. sieveand granulated with a 10% solution of gelatin, containing the suspensionof the active ingredient and washings from the nylon pot, by passingthrough a 16 mesh B.S. sieve. The granules were dried at 40 C.overnight, passed through a 20 mesh B.S. sieve and blended withmagnesium stearate and tabletted using a tabletting machine having ainch fiat-bevelled punch.

EXAMPLE (0) Intra-Articular Injection (a) Preparation of small particleactive ingredient- 2.8 g. Tween 80 was dissolved in ml. of dimethylacetamide (DMA). 12 g. of the active ingredient was then dissolved in130 ml. of this solution and the resulting solution was filteredsuccessively through two dry sintered glass filters (No. 3 and No. 4).

The solution of active ingredient was then added, under asepticconditions, in a fine stream to a stirred sterile aqueous solution ofbenzyl alcohol (10 g. in 1 litre water) over a period of ten minutes.The preparation was allowed to stand for at least three hours and theresulting crystals collected by filtration or centrifuging. Thepreparation was washed with aqueous benzyl alcohol (10 g. in 1 litrewater) and the wet-cake transferred to a well-sealed container. 90% bynumber of the particles had a diameter less than 10p. and none wereabove 50 in diameter.

23 (b) Production of injectable preparation:

Composition: Percent w./v. Fine particle ingredient prepared as in (a)0.50 Hydroxyethyl cellulose 0.40 Benzyl alcohol 1.00 Sodium citrate 0.30Sodium salt of EDTA 1 0.01 Sodium chloride 0.44 Citric acid, q.s.

Water for injection to 100.0 pH value 4.80 to 5.50.

1 EDTA is ethylene diamine tetracetic acid.

(1) Vehicle-The hydroxyethyl cellulose was dissolved in 17.5 litres ofwater for injection using a high speed vortex stirrer. The benzylalcohol was added with stirring. The sodium chloride, sodium citratesalt of EDTA were dissolved in 1 litre of water and added to the bulkvehicle with stirring. The pH value of the bulk vehicle was adjusted to4.80 to 5.50 with a solution of citric acid. The volume was thenadjusted to 19.3 litres and the vehicle clarified by filtration throughnylon. The vehicle was finally sterilised by autoclaving.

(2) Sterile wet-cake of small particle active ingredient prepared as in(:1) containing 100 g. of the active ingredient was added with stirringand under aseptic condtions to 19 litres of the vehcle, and the volumemade up to 20 litres.

The resulting suspension was passed through a sterile 100 mesh BritishStandard sieve and stored in a sealed container. Dosage units forinjection were prepared by aseptically filling neutral glass ampoules orvials closed by a pure latex plug.

What is claimed is:

1. A compound of the formula wherein (a) X represents a hydrogen,chlorine or fluorine atom;

R represents ,B-hydroxy or when X represents a chlorine atom, fl-chloro;R represents a hydrogen atom, methylene or methyl; R represents alkyl of1 to 3 carbon atoms or phenyl, or when R is methylene or methyl, ahydrogen atom; R represents lower alkyl; lower alkyl substituted by atleast one halogen atom or lower alkoxycarbonyl; or (C alkyl substitutedby lower acyloxy; and represents a single or double bond; or

(b) X represents a chlorine or fluorine atom; R represents oxo; Rrepresents a hydrogen atom, methylene or methyl; R represents methyl orethyl; R represents lower alkyl; lower alkyl substituted by at least onehalogen atom or lower alkoxycarbonyl; or (C alkyl substituted by loweracyloxy; and represent a single or double bond.

2. A compound as claimed in claim 1 wherein R represents methyl, ethyl,n-propyl or iso-propyl and R represents methyl, ethyl or propyl.

3. A compound as claimed in claim 1 wherein R represents a hydrogen atomand R represents methyl.

4. A compound as claimed in claim 1 wherein R represents alkyl of 1 to 4carbon atoms.

5. A compound as claimed in claim 1 wherein R represents 3 methyl.

6. A compound as claimed in claim 1 wherein X represents a chlorine orfluorine atom, R represents fi-hydroxy, R represents methyl, Rrepresents methyl, ethyl or npropyl, R represents methyl and representsa double bond.

7. A compound as claimed in claim 6 wherein X represents a fluorine atomand R represents 8 methyl.

8. A compound as claimed in claim 1 wherein X represents a fluorineatom, R represents oxo, R represents {3 methyl, R represents methyl orethyl, R represents methyl and represents a double bond.

9. A compound as claimed in claim 1 wherein X represents a fluorine orchlorine atom, R represents fi-hydroxy,

R represents methylene, R represents methyl, ethyl, n-

R represents methyl, ethyl or n-propyl and R represents methyl or ethyl.

12. A compound as claimed in claim 11 wherein X represents a fluorineatom, R represents 3 methyl and R represents methyl.

13. A compound as claimed in claim 1 wherein X represents a hydrogenatom, R represents ,B-hydroxy and R represents a hydrogen atom ormethyl.

14. A compound as claimed in claim 13 wherein R represents [3 methyl.

15. A compound as claimed in claim 13 wherein R represents alkyl of l to3 carbon atoms.

16. A compound as claimed in claim 13 wherein R represents methyl.

17. A compound as claimed in claim 1 wherein X and R represent chlorineatoms, R represents methyl, R represents methyl or ethyl, R representsmethyl or ethyl and represents a double bond.

18. A compound as claimed in claim 1 selected from the group consistingof 3-oxoandrosta-1,4-diene-l7fi-carboxylate; methyl 9u-diuoro-1 1B-hydroxy-16p-methyl-3-oxo-17apropionyloxy-androsta-1,4-diene-l7B-carboxylate;methyl17a-butyryloxy-9a-fluoro-llfi-hydroxy-lfiflmethyl-3-oxoandrosta-l,4-diene-l7fl-carboxylate;methyl l7a-acetoxy-9a-fiuoro-l lfi-hydroxy-l6a-methyl-3-oxo-androsta-1,4-diene-17fl-carboxylate; methyl 9a-fiuoro-llfl-hydroxy-l6a-methyl-3-oxo-17apropionyloxy-androsta-l,4-diene-17fi-carboxylate;methyl17a-butyryloxy-9a-fluoro-llfi-hydroxy-l6amethyl-Zi-oxo-androsta-1,4-diene-l7fl-carboxylate;methyl 9a-flLlOI0-llB-hydroxy-16-methylene-3-oxol17m-propionyloxy-androsta-1,-4-diene-17,8-carboxyate;

propionyloxy-androst-4-ene-17,8-carboxylate;

methyl l7a-acetoxy-9a-fiuoro-163-methyl-3,ll-dioxoandrosta-1,4-diene-l7fl-carboxylate;

propionyloxy-androsta-1,4-diene-l7p-oarboxy1ate; ethyl 9oz-fiu010-1lfi-hydroxy-16/8-methyl-3-oxo-l7apropionyloxyandrosta-l,4-diene-l7fl-carboxylate; methyl 17a-acetoxy-9a,l1,e-dichloro-16a-methyl-3-oxoandrosta-l,4-diene-17fi-carboxylate; methyl9a-fiu0r0-1lfi-hydroxy-17a-isobutyryloxy-l6-methylene-3-oxo-androsta-1,4-diene-17p carboxylate; ethyl 9a-fil1010-1lfi-hydroxy-17u-isobutyryloxy-l6-methylene-3-oxo-androsta-1,4-diene-17B-carboxylate; methyl1lB-hydroxy-lGit-methyl-3-oxo-l7a-propionyloxy-androsta-1,4-diene-l7B-carboxylate;and

methyl 1lfi-hydroxy-3-oxo-17a-propionyloxy-androst- 19. The compound ofclaim 18 which is methyl 17aacetoxy 9c: fluoro-llfi-hydroxy 16,8methyl-3-oxoandrosta-1,4-diene-17fl-carboxylate.

20. The compound of claim 18, which is methyl 9afiuoro-llfl-hydroxy 16,3methyl-3-0Xo-17a-propionyloxy-andr0sta-1,4-diene-17,8-carboxylate.

21. The compound of claim 18, which is methyl 17ozbutyryloxy 9o;fluoro-llfi-hydroxy-16m-methyl-3-oxoandrosta-l,4-diene-17,8-carboxylate.

22. The compound of claim 18, which is methyl 11,8- hydroxy 16,8methyl-S-oxo-17a-propi0nyloxy-androsta-, 1,4-diene-17p3-carboxylate.

23. The compound of claim 18, which is methyl 115- hydroxy-3-oxo 17apropionyloxy-androst-4-ene-17,8- carboxylate.

References Cited UNITED STATES PATENTS 5 3,579,551 5/1971 Craddock et al260-413 3,636,010 1/1972 Anner et a1. 260-397.1 3,560,558 2/1971Hayakawa et a1. 260514 10 ELBERT L. ROBERTS, Primary Examiner US. Cl.X.R.

P0405) UNITED STATES PATENT OFFICE CERTIFICA'I E OF CORRECTION patent3,828,080 Dated August 3, 11/1374- Inventofls) Gordon Hanley Phillippset al It is certified that error appears in the above-identified patentand that said Letters Patent are hereby corrected as shown below:

Column 15, line 24, should read -2 'Hydroxyethyl-9 -fluoro ll 5-hydroxyl6 5 -methyl3-oxol7 -pro I Column 15, line 62, "on" should read--in-.

Column 16, line 43, "nm." should read --nm (E| 3l5).--.

Column 16, line 45, should be deleted.

Column 20, Example (g) should read as follows:

Example fig} I Active ingredient 0.25% w/v Lanbritol wax* 0.93% w/vDiethylene glycol monostearate 0.65% w/v Cetostearyl alcohol B.P.C.0.65% w/v Liquid paraffin B.P. 1.95% w/v Glycerin I 5 .O% w/v Isopropylalcohol i i 6.5% v/v Methyl p-hydroxy benzoate O. 15% w/v Distilledwater to produce lOO volumes 1. .l

E IFICATE QF CORRECTIQN Patent No. 3 828, 080 Dated August 6 1974Inventor(s) 1 Gordon Hanley Phillipps et al Page 2 7 It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 23, the formula between lines 35 and 49 should show a full lineand a broken line between the land 2-positions rather than two fulllines.

Column 23, lines 51 and 52, should read R represents 6-hydroxy orB-chloro, R being 6 chloro only when X is a chlorine atom-.

Column 23, line 58, z should read Column 23, line 65, z should readColumn 24, line 4, :1: should read Column 24, line 11, z should readColumn 24, line 17, z should read Column 24, line 19, "Compounds" shouldread A compound-- and should read Column 24, line 39, should read Column25, line 1,. "of claim 18 which is" should be deleted.

Column 25, line 4, "of claim 18, which is" should be deleted.

@22 3? UNITED STATES PATENT OFFICE "CERTIFICATE OF CO'RRECTIGN PatentNo. 3, 828 ,080 Dated August 6, 1974 lnventofls) Gordon Hanley Phillippset al p Z It is certified that error appears in the above-identifiedpatent and that said" Letters Patent are hereby corrected as shownbelow;

Column 25, line 7, "of claim 18, which is" should be deleted,

Column 25, line 10, "of claim 18, which is" should be deleted.

Column 25, line 13, "of claim. 18, which is" should be deleted.

Signed and sealed this 1st day of July 1975.

(SEAL Attest C. MARSHALL DANN RUTH C. I-IASON I Commissioner of PatentsAttesting Officer and Trademarks

